The pulmonary effects of STAT3 deficiency

Autosomal dominant hyper-IgE syndrome (AD-HIES) is a syndromic inborn error of immunity (IEI) caused by dominant negative mutations in the signal transducer and activator of transcription 3 (STAT3) gene, impairing the STAT3 protein's activity as a transcription factor.1Freeman A.F. Holland S.M. Clinical manifestations, etiology, and pathogenesis of the hyper-IgE syndromes.Pediatr Res. 2009; 65 (32R-7R)Crossref Scopus (122) Google Scholar The disease features include characteristic facies, rash, recurrent skin infections, recurrent pneumonias, and a variety of connective tissue abnormalities.1Freeman A.F. Holland S.M. Clinical manifestations, etiology, and pathogenesis of the hyper-IgE syndromes.Pediatr Res. 2009; 65 (32R-7R)Crossref Scopus (122) Google Scholar,2Gernez Y. Freeman A.F. Holland S.M. Garabedian E. Patel N.C. Puck J.M. et al.Autosomal dominant hyper-IgE syndrome in the USIDNET tegistry.J Allergy Clin Immunol Pract. 2018; 6: 996-1001Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Recurrent pneumonia and subsequent pneumatocele are typical of the syndrome and are strongly linked to early death.3Freeman A.F. Kleiner D.E. Nadiminti H. Davis J. Quezado M. Anderson V. et al.Causes of death in hyper-IgE syndrome.J Allergy Clin Immunol. 2007; 119: 1234-1240Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar,4Kröner C. Neumann J. Ley-Zaporozhan J. Hagl B. Meixner I. Spielberger B.D. et al.Lung disease in STAT3 hyper-IgE syndrome requires intense therapy.Allergy. 2019; 74: 1691-1702Crossref PubMed Scopus (16) Google Scholar Patients typically develop Staphylococcus pneumonia with subsequent pneumatocele formation, repeated cycles of which lead to infection with Aspergillus and Pseudomonas. This pattern has conventionally been attributed to defective cellular immune protection against Staphylococcus, with subsequent poor wound healing serving as a nidus for molds and gram-negative bacteria that arise later in the disease course.4Kröner C. Neumann J. Ley-Zaporozhan J. Hagl B. Meixner I. Spielberger B.D. et al.Lung disease in STAT3 hyper-IgE syndrome requires intense therapy.Allergy. 2019; 74: 1691-1702Crossref PubMed Scopus (16) Google Scholar In this issue of the Journal of Allergy and Clinical Immunology, Zhang et al examined whether lung epithelial cells carry intrinsic abnormalities that could contribute to this complicated pulmonary course, particularly chronic infection.5Zhang Y. Lin T. Leung H.M. Zhang C. Wilson-Mifsud B. Feldman M.B. et al.STAT3 mutation-associated airway epithelial defects in Job syndrome.J Allergy Clin Immunol. 2023; 152: 538-550Abstract Full Text Full Text PDF Scopus (1) Google Scholar Their findings suggest that we may be underestimating the degree to which somatic cell types and primary pulmonary abnormalities may be contributing to the significant lung susceptibility and injury seen in patients with AD-HIES. Prior investigation of the role of STAT3 in the function of nonhematopoietic cells has identified important participation in coordinated responses to injury and cellular differentiation. Its role in tissue healing was recently investigated by Dmitrieva et al, who identified deficient support of angiogenesis by patient fibroblasts and abnormal organization of the extracellular matrix in patient coronary arteries.6Dmitrieva N.I. Walts A.D. Nguyen D.P. Grubb A. Zhang X. Wang X. et al.Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome.J Clin Invest. 2020; 130: 4167-4181PubMed Google Scholar Its role in osteoblast differentiation was also recently explored by Zhou et al in mouse models of STAT3 deficiency.7Zhou S. Dai Q. Huang X. Jin A. Yang Y. Gong X. et al.STAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis.Nat Commun. 2021; 12: 6891Crossref PubMed Scopus (20) Google Scholar With regard to pulmonary manifestations, Hokuto et al showed that mice with STAT3 deletions in respiratory epithelium experienced more rapidly progressive lung injury and had abnormal alveolar capillary integrity, surfactant deficiency, and poor pulmonary mechanics, leading to epithelial and vascular injury.8Hokuto I. Ikegami M. Yoshida M. Takeda K. Akira S. Perl A.K.T. et al.Stat-3 is required for pulmonary homeostasis during hyperoxia.J Clin Invest. 2004; 113: 28-37Crossref PubMed Scopus (109) Google Scholar Tadokoro et al showed that the IL-6/STAT3 pathway favored formation of ciliated airway epithelial cells over secretory cells, with dominant negative STAT3 mutations leading to a similarly significant decrease from baseline.9Tadokoro T. Wang Y. Barak L.S. Bai Y. Randell S.H. Hogan B.L. IL-6/STAT3 promotes regeneration of airway ciliated cells from basal stem cells.Proc Natl Acad Sci U S A. 2014; 111: E3641-E3649Crossref PubMed Scopus (190) Google Scholar Zhang et al5Zhang Y. Lin T. Leung H.M. Zhang C. Wilson-Mifsud B. Feldman M.B. et al.STAT3 mutation-associated airway epithelial defects in Job syndrome.J Allergy Clin Immunol. 2023; 152: 538-550Abstract Full Text Full Text PDF Scopus (1) Google Scholar differentiated respiratory epithelial cells from a variety of sources to identify developmental and functional perturbations associated with STAT3 dysfunction. In an air-liquid interface culture, STAT3 deficiency resulted in a skewed composition of epithelial cells, with fewer ciliated cells and increased numbers of goblet cells and club cells (Fig 1). Mucociliary clearance rate was diminished, and differentiated epithelial cultures demonstrated a higher degree of adhesion of Pseudomonas aeruginosa to the airway epithelial cell layer with the STAT3 mutations than in the controls (Fig 1), as well as increased survival of P aeruginosa after 4 hours. To explain this phenomenon, Zhang et al5Zhang Y. Lin T. Leung H.M. Zhang C. Wilson-Mifsud B. Feldman M.B. et al.STAT3 mutation-associated airway epithelial defects in Job syndrome.J Allergy Clin Immunol. 2023; 152: 538-550Abstract Full Text Full Text PDF Scopus (1) Google Scholar identified decreased secretion of the antimicrobial peptide BPFA1, decreased expression of a number of inflammatory cytokine genes (IL1A, IL1B, IL6, IL17C, TNFA, CXCL1, CXCL2, CXCL13, CCL2, and CCL20), and impaired transmigration of neutrophils across the air-liquid interface culture from a patient with AD-HIES following exposure to P aeruginosa. These findings suggest that in addition to impaired pulmonary tissue repair after infections leading to lung injury, patients with AD-HIES have intrinsic respiratory epithelial mechanical and inflammatory defects that contribute to their known susceptibility to infection. Furthermore, another implication could be that decreased expression of cytokines may affect baseline epithelial function even in the absence of infection. Zhang et al5Zhang Y. Lin T. Leung H.M. Zhang C. Wilson-Mifsud B. Feldman M.B. et al.STAT3 mutation-associated airway epithelial defects in Job syndrome.J Allergy Clin Immunol. 2023; 152: 538-550Abstract Full Text Full Text PDF Scopus (1) Google Scholar did not evaluate the effect of abnormal cytokine profiles on mucosal function and maintenance, such as for example, the effect of IL-13 on mucus production or the effect of IL-22 on production of defensins and maintenance of epithelial barrier function. This may be a potential area for further study. The mainstay of therapy for patients with AD-HIES is antimicrobial prophylaxis to minimize the risk of infections and thereby decrease the progression of disease by minimizing tissue injury. With the implication of primary pulmonary epithelial cell defects, we are presented with a new potential therapeutic target for the life-limiting lung disease seen in these patients. As Zhang et al5Zhang Y. Lin T. Leung H.M. Zhang C. Wilson-Mifsud B. Feldman M.B. et al.STAT3 mutation-associated airway epithelial defects in Job syndrome.J Allergy Clin Immunol. 2023; 152: 538-550Abstract Full Text Full Text PDF Scopus (1) Google Scholar suggested, STAT3-directed gene therapies may be an option to which we can look in the future, and we may also consider whether correction of the abnormal pulmonary cytokine profile with inhaled therapies could be of benefit. Additionally, given the decreased mucociliary clearance with an increased proportion of mucus-producing cells, it is possible that using preventive airway clearance and inhaled prophylaxis regimens, as has been used in patients with cystic fibrosis (CF) for many years, could also be of some benefit for patients with AD-HIES. These parallels to CF and its management were previously highlighted by Kröner et al, who also suggested a quarterly monitoring scheduled similar to that used for CF.4Kröner C. Neumann J. Ley-Zaporozhan J. Hagl B. Meixner I. Spielberger B.D. et al.Lung disease in STAT3 hyper-IgE syndrome requires intense therapy.Allergy. 2019; 74: 1691-1702Crossref PubMed Scopus (16) Google Scholar Although this article elevates the role of the respiratory epithelium in AD-STAT3 deficiency, the role of hematopoietic cell dysfunction must also be considered. Harrison et al reported stabilization of lung disease in 8 patients with AD-HIES who underwent hematopoietic stem cell transplantation in childhood,10Harrison S.C. Tsilifis C. Slatter M.A. Nademi Z. Worth A. Veys P. et al.Hematopoietic stem cell transplantation resolves the immune deficit associated with STAT3-Dominant-negative hyper-IgE syndrome.J Clin Immunol. 2021; 41: 934-943Crossref PubMed Scopus (17) Google Scholar suggesting that systemic immune function still plays a dominant role in AD-HIES lung disease. Therefore, lung transplantation should still be approached with caution, particularly given the significant systemic disease and known defects of vascular and connective tissue remodeling in these patients. Nonetheless, the findings of Zhang et al5Zhang Y. Lin T. Leung H.M. Zhang C. Wilson-Mifsud B. Feldman M.B. et al.STAT3 mutation-associated airway epithelial defects in Job syndrome.J Allergy Clin Immunol. 2023; 152: 538-550Abstract Full Text Full Text PDF Scopus (1) Google Scholar suggest that the host lungs of patients with AD-HIES could retain a susceptibility to infection following hematopoietic stem cell transplantation. It is hoped that patients who receive a transplant and undergo long-term follow-up will inform us as to whether that is the case. And for the majority of patients who have not received a transplant, direct respiratory targeted therapies that augment the dampened response to infection are an alluring proposition. Lung diseases in primary immunodeficiency disease can be attributed to a variety of factors, with the most-cited culprits being parenchymal damage due to frequent and severe infections or due to autoinflammation caused by an aberrant and often dysregulated immune system. Significantly less attention is paid to development and maintenance of the lung epithelium. The findings reported by Zhang et al5Zhang Y. Lin T. Leung H.M. Zhang C. Wilson-Mifsud B. Feldman M.B. et al.STAT3 mutation-associated airway epithelial defects in Job syndrome.J Allergy Clin Immunol. 2023; 152: 538-550Abstract Full Text Full Text PDF Scopus (1) Google Scholar highlight the important fact that the defects leading to immunodeficiencies can cause systemic tissue abnormalities beyond the sequelae of infections and tissue injury. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. STAT3 mutation-associated airway epithelial defects in Job syndromeJournal of Allergy and Clinical ImmunologyVol. 152Issue 2PreviewJob syndrome is a disease of autosomal dominant hyper-IgE syndrome (AD-HIES). Patients harboring STAT3 mutation are particularly prone to airway remodeling and airway infections. Full-Text PDF